The anti-CEACAM1 agonistic antibody CCM5.01 inhibits the growth of colon cancer cell lines in 2D and 3D models

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Abstract Background Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is an inhibitory receptor expressed by multiple tumors, including colorectal cancer (CRC). CEACAM1 exists as a long isoform (L) containing immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and a short isoform (S) lacking ITIMs. While microsatellite instability (MSI) CRCs respond to immunotherapy, microsatellite-stable (MSS) CRCs remain resistant, highlighting the need for alternative therapeutic targets. We previously developed an agonistic anti-CEACAM1 monoclonal antibody (mAb), CCM5.01, and demonstrated its CEACAM1-dependent inhibitory effects in melanoma. Here, we evaluated CCM5.01 inhibitory activity on CRC cell lines and related it to L/S ratio. Methods CRC cell lines HT-29, LOVO, and HCT-116 were treated with CCM5.01 and analyzed by proliferation assays before and after transfection with L or S CEACAM1 isoforms. Transfected cells treated with CCM5.01 were analyzed for signaling and in 3D spheroid models. Results CEACAM1-positive CRC cells showed dose-dependent inhibition in response to CCM5.01 treatment and were associated with L/S isoform expression. High CEACAM1-L expression induced growth inhibition and apoptosis, while CEACAM1-S promoted cellular activity. Similar isoform-dependent effects were observed in spheroid models. Conclusions CEACAM1-mediated signaling in CRCs critically depends on the L/S isoform ratio, supporting CEACAM1-targeted activating therapy as a potential strategy in both MSI and immunotherapy-resistant MSS CRC.